This comprehensive plan to develop a research career in the treatment of oral, pharyngeal and head and neck cancer (HNSCC) focuses on hypothesis-driven cancer gene therapy research. The candidate's long-term goal is to develop innovative regimens for the treatment and chemoprevention of HNSCC based on understanding of the molecular mechanisms that provide survival advantages to these tumors. Immediate goals of gaining technical expertise through supervised experiments and advanced workshops will be met in facilities that provide for complete execution of cancer gene therapy studies from benchtop to bedside. The candidate will fully develop through this mentored award the new research skills and knowledge necessary to succeed as an independent investigator in the area of cancer gene therapy. HNSCC is the 6th most common cancer in the world. The development of effective molecular treatment is desirable to minimize the deformities of speech, swallowing and cosmesis associated with current conventional treatments. Preliminary studies show a clear role for ATF2 in survival and cytokine production in HNSCC. Using the transcription factor ATF2 as a target in HNSCC, the study will address the following Specific Aims: (1) Demonstrate that ATF2 is expressed and transcriptionally active in a constitutive fashion and can also be induced by various treatments. This aim will determine the nature and patterns of ATF2 expression and function as it relates to other transcription factor subunits. (2) Demonstrate that reduction of ATF2 function and AP-1 activity results in the following phenotypic changes: a) decreased production of cytokines, b) TNF-a mediated cytotoxicity, c) decreased production of inhibitors of apoptosis, and d) alterations of cell cycle progression (3) Show that ATF2 dominant negative delivered by intratumoral gene therapy safely and effectively impairs HNSCC survival; TNF-slpha inhances the efficacy of ATF2 dominant negative treatment. Experiments in this study will prove that localized, molecular treatment of tumors targeting ATF2 can enhance susceptibility of HNSCC to treatments and decrease conditions favorable for pregression and metastasis. These studies will demonstrate the clinical potential of targeting ATF2 using gene therapy. Therapeutic efficacy targeting this mechanism in humans will be the aim of future studies by this investigator.